Hydrogenation of thiophene compounds



Patented Nov. 8, 1949 UNITED. STATES PATENT omen HYDROGENATION OF THIOPHENE COMPOUNDS Stanton A. Harris, Westfield, Karl Folkers, Plainfield, Ralph Mozingo, Elizabeth, and Glen E. Arth, Rahway, N. J., assignors to Merck & 00., Inc., Rahway, N. J a corporation of New Jersey No Drawing. Application September 16, 1944, Serial No. 554,455

12 Claims. (Cl. 260-329) It is now found that this compound can be synthesized by reactions indicated as follows:

NE: NH: H-OOaH' mar-001E XCHlOOi I m-sn m-s-omooni 1 BOOK 7 m zo nc io NH NH m-cola ROE in-com m-s-omoom Hrs-011100211 (3) lRoM RCO 3([30 n NH 1% Ho 11+, 11,0 JH-C l (5 heat CHr-S- COIR Hz-S- H1 O=CH(CH2)3CO2R Boo Boo NH a l wn N11101: NH o H--C JJHJ3 II HN-C-NH In the above formulae, R represents an alkyl, aryl or arylalkyl group; X, a halogen; and M an alkali metal or an alkaline earth metal.

The reactions above indicated are conducted as follows: 2-amino-3-mercapto propanoic acid (1) and chloroethanoic acid are condensed in an alkaline aqueous solution to form 2-amino-3- carboxymethylmercapto-propanoic acid (2); which is then treated with an acylating agent, such as an acyl halide, in an aqueous alkaline solution to yield 2-acylamido-3-carboxymethy1- mercapto-propanoic acid (3). This product is esterified using a mineral acid catalyst to produce the diester (4) of the acid (3), and the diester is treated with alkali metal alcoholate or an alkaline earth metal alcoholate to yield the 2-alkali metal or the 2-alka1ine earth metal derivative of an ester of 2-carboxy-3-keto-4- acylamido-tetrahydrothiophene (5). This compound, When heated with a dilute mineral acid, is hydrolyzed and decarboxylated to produce 3-keto-4-acylamidotetrahydrothiophene (6) which, when reacted with 4-carboxybutanal ester in a lower aliphatic alcohol reaction me-, dium containing piperidine and a lower aliphatic carboxylic acid, produces 2-(4-carboalkoxy- :butylidene) -3-keto 4 acylamido tetrahydrothiophene (7). This product, when reacted with hydroxylamine yields an ester of the corresponding oxime, 2 (4' -carboXy-buty lidene) 3- isonitroso-lacylamidoetetrahydrothiophene (8) which upon treatment with a mixture of zinc, a lower aliphatic acid and a lower aliphatic, acid anhydride, produces an equilibrium mix-' ture of 2- (4-carboXy-butylidene) -33 4%dii(a.cyl'; amido)-tetrahydrothiophene ester (9a) andi 2i- (4-carboXy-butyl) -3:4-di(acylamid o 415,- dihydrothiophene ester (9b)., This equilibrium mixture, or if preferred, one of theequilibrants, is then treated with hydrogen in the; presence of a hydrogenation catalyst to yield 2-(4'-car boxy-butyD-3 4-di(acylamido)-tetrahydr0tlii: ophene ester (10). When this last mentioned compound is treated with an aqueous; alkaline solution, hydrolysis of the acyl groups occurs, yielding upon acidification, 2- (4'-carboxy -butyl) 3 :4-diamino-tetrahydrothiophene (1 l) which, when reactedi withia carbonyl halide, produces the compound 2: (4 -carboxy-butyl) -3 :4 -ureid'e tetrahydrothiophene; This product is obtained as a mixture of 'stereoisomers, one of which is racemic biotin, from which upon resolution, is obtained. the. dextrorotatory. isomer, biotin? This invention is concerned generally with compounds of the class of which intermediate above is a member, the 2-(4-carboxy-butyl) 3 4-di (acylamido) -tetrahydrothiophenes and esters thereogt; and particularly with the compounds represented by the gformula:

wherein R and R are diflerent acyl groups and R" is of the ;class consistingoihydrogen, alkyl, aryl, and arylallsylgroupsg According to the present'mvention, compounds represented by this formula ;are prepared by hydrogenation in the presence of a hydrogenation catalyst, of a compound represented by the formula:

na er'r mcms om" or'its eq uilibrant'represented bwtheformula;

RN Hi- RIN H;

H I ie komm 013 wherein R; R. and-f3. have the' significance as signed above; It presently preferred where practicing the 4 process; according to; this inveng tionto use a hydrogenation catalyst comprising a metal; of the platinum group; particularly" platinumandfor 'palladilm' It is preferredigthat tl'ie catalyst be. distributed' upon, af suitable c rierfsuch as charcoal suspendedin" the reaction; medium; and that the reaction be conductedi injailiquid' medium such" as an organic solvent? The starting material canbe obtained by the reactions indicated above andjdescribed' intdeg tail inconcurrently filed applicationsserial 1 Nos,1 5543458- nowPa-tent 2,456,232; 554, 44 55,414.50; 554;4511 55'4j452" now; Patent: 2,452,653? 554453" now Patent 2,460,224; and-"554,454 now; Patent 23593317 'theproduct obtained bythe process;

according to this invention can be converted to biotin by the operations indicated above and described in concurrently filed applications Serial Nos. 554,456 and 554,457, both now abandoned.

hen. h m d, sMir om t ybutylideneifi. 3 g-aeetamidog- 4; -berrzamido;-tetrahydrothiophene is'"prep'ared' by synthesis, it is obtained as a mixture of isomers which can be readily separated by fractional crystallization, 105 aafirstgracemateeof stereo-isomers (M. P. 185- 1869 -C.) consisting of the dextrorotatory and laevorotatory forms of the equilibrant 2-(4'- carbomethoxy-butyll- 3 -acetamido- 4 -benzamido 4; i5gdihydrothiophene and a second race- ;mateofstereolsomers (M. P. 162-163 C.) con-- sisting of the dextrorotatory and laevorotatory forms-i of 2=(4 carbomethoxy-butylidene) -3- acetamido- 4 -benzamido tetrahydrothiophene. The;;first racemate, when subjected to catalytic hydrogenation according, to the process accordnag hirst nye tiop y'cld a r! ff, csmi Ste r -c amuiwt hyd othio he e, .;P,,153-42,o, racemaile, when; subjected; to; such, hydrog onr l io yieliis' aha .f

3 ,stereoisomersfthe dl-tran's-allo lsbmefiMg. 1'72-173 C.) above mentioned and the dl-tr'a'ns epiallo-Z- (4'carbomethoxy-butyl) 3 -acetamido- 4-benzamido-tetrahydrothiophene,r (M P. 185 6 (3.). H

Inasmuch as the catalyticreductiom reaction according to: this inventiom isnot: concerned a with the acylamido substituents, it is not material: whati-acyli gmups alipeazrointhese; substituents provided'ilrowevenathat the:azeyllgroir'pssar'et,-

4o., ,diflerent. Among the acyl groups that can appear at these substituents are acetyl, propanoyL butanoyl, benzoyLa-rrd othenacyl groups derived from allzyl. carboxylic acids'iarylcarboxy acids and arylalkylicarboxylic acids. It is also imma- 45,,terial what esters are employed as all are satis- "factory,;;in cl;uding methyl, ethyl, propyl, butyl, benzyl, phenyl and other alkyl, aryl and arylalkyl esters.

The following examples illustrate a method of 56 carrying out the present invention, but it j-is to be understoodzthat thesegeigamples aragiren by way of.,.il1ustration iamd not oi limita on.

Example 1 sill oumpio 015130 0 About 1.1 g. of dl-2-(4-carbomethoxy-butyl)- 3-acetamido-4 benzainid'o 4:5 dihydro thioi; V phene (M. P. 185-186??G.) isiadded oiazsusp l'rrsion of about 71g of palladinized (about 5% activated charcoal, previously reduced with m drogen, in'ab'out-'126cc.' of methanol' and hydro gen is passed-into the mixture at room itemperature. After absorption of the calculated quanti- 75 ty of hydrogen, which usuallwreqimies about 20 Example 2 The operations described in Example 1 are repeated but after the hydrogenation step the catalyst is removed, extracted with chloroform, the extract is evaporated to dryness, and the residue is crystallized from ether to yield the product dl-cis-2- (4-carbomethoxy-butyl) -3 acetamido- 4-benzamido-tetrahydrothiophene (M. P. 153- 154? 0.). When this product is saponified and acidified aS in Example l, the corresponding d1- cis-acid (M. P. 232 C.) is obtained.

Example 3 The operations described in Example 2 are repeated using dl-2- (4'-carbomethoxy-butylidene) 3-acetamido-4-benzamido tetrahydrothiophene (M. P. 162-163 C.) instead of the starting material' therein indicated. The product obtained is dl-trans-epi-allo-2 ('ecarbomethoxy-butyl) 3-acetamido-4- benzamido tetrahydrothiophene (M. P. 185-186" 0.).

Example 4 The operations described in Example 1 are repeated using a palladium-barium carbonate catalyst instead of a palladium charcoal catalyst. The product (M. P. 171-172 C.) is identical with that obtained as described in Example 1. Evaporation of the methanol filtrate yields the dl-cisisomer (M. P. 153-4 0.).

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof and the invention is to be limited only by the appended claims.

What is claimed is:

1. The process which comprises reacting. a compound represented by the formula:

wherein R and R are different acyl groups and R" is a radical selected from the group which consists of alkyl, aryl and arylalkyl radicals, with hydrogen in the presence of a hydrogenation catalyst selected from the class which consists of metals of the platinum group, to produce a compound of the formula:

wherein R, R and R" have the significance above defined.

2. The process which comprises reacting '2(4'- carboaroxy butyl) 3 acetamido-l-benzamido- 4:5-dihydrothiophene with hydrogen in the presence of palladium catalyst to produce 2(4'-carboaroxy butyl)-3-acetamido-4-benzamido tetrahydrothiophene.

3. The process which comprises reacting 2(4 carboaralkoxy butyl) -3-acetamido'-4-benzamido- 4:5-dihydrothiophene with hydrogen in the presence of palladium catalyst to produce 2(4'-carboaralkoxy butyl) -3-acetamido-4-benzamido tetrahydrothiophene.

4. The process which comprises reacting 2(4'- carboalkoxy butyl) 3 acetamidoi-benzamido- 4:5-dihydrothiophene with hydrogen in the presence of palladium to produce 2(4'-carboalkoxy butyl)-3-acetamido-4-benzamido tetrahydrothiophene. a

5. The process which comprises reacting 201- carbomethoxy butyl) -3-acetamido-4-benzamido- 4:5-dihydrothiophene with hydrogen in the presence of palladium to produce 2(4'-carbomethoxy butyl)-3-acetamido-4-benzamido tetrahydrothiophene.

6. The process which comprises reacting a compound represented by the formula:

wherein R and R are different acyl groups and R" is a radical selected from the group which consists of alkyl, aryl and aryl-alkyl radicals, with hydrogen in the presence of a hydrogenation catalyst selected from the'class which consists of metals of the platinum group, to produce a compound of the formula:

wherein R, R and R have the significance above defined.

7. The process which comprises reacting a compound represented by the formula:

wherein R and R are different acyl groups and R" is a radical selected from the group which consists of alkyl, aryl and aryl-alkyl radicals, with hydrogen in the presence of palladium to produce a compound of the formula:

ido tetrahydrothiophene with hydrogen in the.

presence of palladium to produce 2(4'-carboa1- 73 koxy; butiyl)1 3ea'eetamidoeeebenzamidb: tetrahye drothiophene.

102 Thaprocesswlfich comprisesmeacting12'(4- carbomethoxybutylideneiy- 3- azcetamidne i benz,

amido: tetral'iydrothiophene?witlfnhydrogen in" the presence of" are hydrogenation catalyst: selected?- from the class: WhiChLCUnSiSt'S; oi? metalsaofm the platinum group, to produce 2(41fi-carbomethoxy butyl) -3ea.ceta;mida :4ebenzamido tetrahydiothiophene."

11;. The: process;whichicomprises .reactingtZiMi- I carhomethoxybutylidenefi 3 acetamidoeeebenze amidoitetrahydrothiophenelwithahydrogeminithez presence of palladium to produce 2(4'-carlm' methoxgmbutyl') -3.=acetamidoe iebenzamido:tetrahydrothiophene:

12;.,The: process which comprisesttreacting a: compound selectedifromw the -=:c1ass.-'-consisting:; of;

wherein R and-R are different acyl groups-and R""is--a radical *sel'ecteti from the'class which consists of elk-Y1," aryl andiarylvlkyr radicais;with

hydrogen the" presence? of; a; hydrogenation cataiyst*selected'-from the cissewhichiconsist's "of metalsiomnep anmimigmup :mipmauaeieaconie p unds; of. :the: formulae.

The following references are of record in the fil: ofmis" patent:

UNITED? ST AT-ESr'IPA'I'ENTS- Nfimber Nme 2233;999" Harlow" M9114; 1941i? OTHER: REFERENCES 7 Berkmanr Catalysis; 'pag'es '8 31 -a nd 843; hold Piibz eoe, Ni-YJ, 1940.

Richter: Organic Ghemistry-r pages 645K505 Wiley, N. Y., 1938. v

Karrer: Organic Chemistry; page 428, Nameman N: Y.",-,1938

Morton: The-*Ch'emistryrof Heterocyclic: Com-1 pounds-,cpage- 7 McGraweI-IiH; ,N:Y;,-.1946u2 Ailesz-a: J.-:1Phairm.1 Exp::JI-'her.,:, 721 1 2653 (1941);;

Rein= 

